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Results of Sofosbuvir Plus Ribavirin in Patients With Hepatitis C Related Decompensated Cirrhosis
Accepted Manuscript Title: Results of sofosbuvir plus ribavirin in patients with hepatitis c related decompensated cirrhosis Author: Naveen Tmu Ashish Kumar Praveen Sharma Vikas Singla Naresh Bansal Anil Arora PII: DOI: Reference:
S0973-6883(18)30040-9 https://doi.org/doi:10.1016/j.jceh.2018.02.009 JCEH 525
To appear in: Received date: Revised date: Accepted date:
2-7-2017 31-1-2018 20-2-2018
Please cite this article as: https://doi.org/10.1016/j.jceh.2018.02.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
RESULTS OF SOFOSBUVIR PLUS RIBAVIRIN IN PATIENTS WITH HEPATITIS C RELATED DECOMPENSATED CIRRHOSIS Naveen TMU, Ashish Kumar, Praveen Sharma, Vikas Singla, Naresh Bansal, Anil Arora
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Short title: Sofosbuvir plus ribavirin in decompensated cirrhosis
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Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
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Total number of Tables: 4 Number of figures: 3 Source(s) of support: Nil Conflict of interest: None
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Correspondence: Prof. Anil Arora, MD, DM Chairman Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences Ganga Ram Institute for Postgraduate Medical Education & Research (GRIPMER) Sir Ganga Ram Hospital Rajinder Nagar New Delhi, 110 060 India Email: [email protected] Fax: +91-11-25861002
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KEYWORDS Sofosbuvir; direct acting antivirals; decompensated cirrhosis; ascites; HCV
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ABSTRACT BACKGROUND: Sofosbuvir (SOF), a direct acting antiviral (DAA), has revolutionized the
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treatment of chronic hepatitis C virus (HCV) infection. However, data is scarce about efficacy of
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SOF plus ribavarin (RBV) in Indian patients with decompensated cirrhosis. We evaluated the efficacy of SOF plus RBV in decompensated cirrhosis, and compared the outcome with
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compensated cirrhosis and non-cirrhotics.
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PATIENTS AND METHODS: Consecutive decompensated cirrhotic patients of chronic HCV with detectable HCV RNA were treated with 24-week course of SOF (400 mg) plus weight based RBV.
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SVR, CTP and MELD scores were assessed at 36 weeks (i.e. 12 weeks after completion of therapy). Non-cirrhotic chronic hepatitis C patients and patients with compensated cirrhosis
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treated with SOF plus RBV during the same period were used as controls. During the period of
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this study Ledipasvir and Daclatasvir were not available in India. RESULTS: A total of 47 patients [median age 50 (29-82) years, 64% males] with decompensated cirrhosis were included as ‘cases’ in the study; while, 27 patients with compensated cirrhosis and 29 patients with chronic hepatitis were included as ‘controls’. Age, gender, HCV RNA levels, and genotype distribution were similar in cases and controls. The median CTP and MELD scores of cases were 8 (7-12) and 13 (6-25), respectively. Among cases 39 (83%) could complete the therapy, while 1 (2%) was intolerant and 7 (15%) died before completion of therapy. ETR was achieved in 37/39 (95%) cases. Of these, another 3 died before SVR, and 7 failed to achieve SVR, thus 27/34 (79%) could achieve SVR. Thus according to intention-to-treat analysis, only 27/47 (57%) cases could achieve SVR. In comparison, 24/28 (86%) compensated cirrhotics and
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27/28 (96%) of chronic hepatitis achieved SVR. There was a significant improvement in mean CTP score in cases who achieved SVR (p<0.01) compared to those who did not achieve SVR/ETR. On multivariate analysis the only independent factor influencing successful outcome patients
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was a serum albumin >3.5 g/dL.
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CONCLUSIONS: A 24-week course of Sofosbuvir plus Ribavirin in decompensated HCV cirrhosis could lead to SVR in only 57% of patients. The failure of therapy in 43% patients was either due
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to non-response, intolerance, or death. A serum albumin of more than 3.5 is associated with
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success of antiviral therapy. Thus an early initiation of antiviral therapy is recommended before
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decompensation sets in as it precludes successful outcome.
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INTRODUCTION
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It is estimated that around 170 million people worldwide are affected with the Hepatitis C virus (HCV) infection1. HCV infection leads to a slowly progressive liver disease. Cirrhosis occurs
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usually around 20-30 years after the infection2. The rate of decompensation is 3.9% per year,
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and the hepatocellular carcinoma (HCC) rate is 3% per year3. As most patients are
asymptomatic for several years, early diagnosis remains a challenge. Stabilization of the liver
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functions is an important goal among both groups of compensated HCV infection and decompensated patients, who are not candidates for liver transplantation, whereas, prevention
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of HCV recurrence is the goal in post-liver transplantation patients4. Sustained virological response (SVR) is tantamount to cure in anti-HCV treatment. SVR at
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present is defined as aviremia 12 weeks after the completion of antiviral therapy for chronic HCV infection5,6,7. Till recently Interferon (IFN) based treatment was the standard of care in anti-HCV treatment. Direct Acting Antivirals (DAA) were the major breakthrough in the treatment of HCV infection. Sofosbuvir is an important DAA, present in almost all DAA regimens. Multiple studies have shown that the efficacy of IFN-free regimens, as studied in different phase-3 trails is >95% SVR rate in patients with chronic hepatitis and compensated cirrhosis8,9. However data regarding efficacy of DAAs in decompensated cirrhosis patients
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scarce, especially from India. This study was undertaken to study the efficacy of Sofosbuvir plus Ribavarin in decompensated HCV cirrhosis patients from India.
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PATIENTS AND METHODS
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Study Setting The study was conducted from May 2015 to June 2016, in patients attending inpatients or
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outpatients’ department of Sir Ganga Ram Hospital, New Delhi. The Ethics Committee of the hospital approved the study and a written informed consent was obtained from all the
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participants. The study conformed to the Helsinki declaration of 1975 as revised in 1983.
Inclusion Criteria
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Patients
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Consecutive decompensated cirrhotic patients of chronic HCV with detectable HCV RNA were
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included in the study as ‘cases’. Decompensated cirrhosis was defined as Child B or C with history of ascites, encephalopathy, UGI bleed secondary to varices, or jaundice. Non-cirrhotic chronic hepatitis C patients and patients with compensated cirrhosis treated with SOF plus RBV during the same period were used as ‘controls’. Both cases and controls were ≥18 years old.
Exclusion Criteria
Patients with pregnancy; glomerular filtration rate (GFR) less than 30 mL/min; HBV or HIV Coinfection; hepatocellular carcinoma; expected life span of less than one year due to various comorbidities; refusal to participate; contraindication to the use of Ribavarin; and patients on
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anticonvulsants (phenytoin, carbamazepine), Rifabutin, Rifampicin, Amiadarone were excluded
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from the study.
Evaluation
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Each patient underwent detailed evaluation in form of history, physical examination, and
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relevant investigations. History of previous upper and lower GI bleeds, hepatic encephalopathy, ascites, other co-morbidities like diabetes, hypertension, HIV, hepatitis B, chronic kidney
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disease, liver or kidney transplantation were obtained from all patients. History of current use of amiadarone, carbamazepine, phenytoin, rifampicin, and rifabutin were also obtained. Past
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history of medication use for HCV, its details with outcome were taken. All patients underwent following investigations: CBC, LFT, RFT, HBsAg, HIV, USG abdomen, Fibroscan, UGI endoscopy,
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HCV RNA quantitative analysis, and HCV genotype.
Treatment Protocol and Follow-up
All patients (cases and controls) were started with Sofosbuvir and Ribavarin with the intention of 24 weeks of treatment. During the period of this study Ledipasvir and Daclatasvir were not available in India. Female patients of reproductive age group were cautioned not to become pregnant while receiving Ribavirin containing antiviral regimens, and up to 6 months after stopping. Follow-up was done through direct patient visit, telephone call, or email. Follow up was done at 4, 12, 24, and 36 weeks (i.e. 12 week after treatment completion). During each visit patients were assessed for clinical improvement or deterioration and any adverse effects. In
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addition to these scheduled follow-ups, patients also visited or called as and when needed depending on patients’ clinical status. The dose of Ribavarin was modified on follow-up if
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patient developed anemia at any time.
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Primary Objective
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The primary objective of the study was to compare the SVR rate in cases and controls at 12
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weeks from end of treatment.
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Secondary Objectives
The secondary objectives of the study were to assess change in CTP and MELD scores at 12
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influencing achievement of SVR.
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weeks after completion of the treatment in decompensated cirrhosis and to study factors
Statistical Analysis
Continuous data were expressed as median (range) and compared using Mann Whitney U test or Wilcoxon signed rank test. Categorical data were expressed as number (%) and compared using Fisher’s exact test or Pearson chi square test. A p value <0.05 was considered significant. Statistical analysis was conducted using the SPSS 17.0 statistical package (SPSS Inc, Chicago, IL, USA).
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RESULTS
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Patients From May 2015 to June 2016, a total of 55 patients with decompensated cirrhosis with HCV
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infection were screened for the study. However 8 patients were excluded due to following
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reasons: (i) GFR less than 30 mL/min (n=3); (ii) HBsAg or HIV co-infection (n=2); (iii) HCC (n=2); and (iv) Refusal to participate (n=1). Thus remaining 47 patients were included in the study as
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‘cases’. During the same duration, 28 patients of compensated cirrhosis due to HCV and 28 patients of non-cirrhotic chronic hepatitis C were included in the study as ‘controls’.
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The baseline characteristics of included patients are given in table 1. The age, gender
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distribution, genotype, HCV RNA, and prior treatment history were similar in cases and controls.
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The median CTP and MELD scores of cases were 8 (range 7-12) and 13 (6-25), respectively; and these were significantly worse than in controls. Ascites was present in 66% of cases, while none of the controls had ascites. Bilirubin, albumin, INR, hemoglobin and platelet levels were significantly worse in cases as compared to controls.
Treatment and results
All patients (cases and controls) were started with Sofosbuvir and Ribavarin with the intention of 24 weeks of treatment. Among the 47 patient of decompensated cirrhosis group, one patient was intolerant to the antiviral therapy; hence, it was stopped. Remaining 46 patients continued with therapy, however, 7 patients died before completion of 24 weeks of treatment. The cause
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of these deaths were advanced liver disease. Thus a total of only 39 (83%) patients of 47 could complete the 24 weeks of treatment, and these were assessed for ETR. Thirty-seven out of 39 patients (95%) achieved ETR and 2 patients (5%) did not achieve ETR. During follow-up of next
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12 weeks, additionally 3 patients died. Thus only 34 (92%) of 37 patients who had achieved ETR
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could be assessed for SVR. Of these 34 patients only 27 (79%) could achieve SVR and rest 7 (21%) could not achieve SVR.
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Among controls, all 27/28 (96%) patients with compensated cirrhosis could complete 24 weeks
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of therapy, while one patient died due to development of rapid decompensation following HCC (which was not detected at baseline). All the remaining 27 patients (100%) who completed
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therapy achieved ETR. After 12 week follow up 24/27 (89%) could achieve SVR and 3/27 (11%) could not achieve SVR. Of 28 patients with chronic hepatitis (non-cirrhotics), all (100%) could
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complete 24 weeks of therapy. These 28 patients were assessed for ETR and 27 (96%) achieved
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ETR; and of these 27 patients assessed for SVR, all of them (100%) achieved SVR. Thus according to intention-to-treat analysis only 27 (57%) out 47 decompensated cirrhotics (cases) could achieve SVR and the rest 20 (43%) failed therapy either due to non-response, intolerance or death. In contrast 24/28 (86%) of compensated cirrhosis and 27/28 (96%) of chronic hepatitis were able to achieve SVR.
Factors influencing success of therapy Out of the total cohort of 103 patients (47 cases and 56 controls), 78 (76%) had successfully achieved SVR, while rest 25 (24%) failed the therapy due to following reasons: non-response
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(n=13), intolerance to therapy (n=1), and death (n=11). Various baseline factors were analyzed to determine which factors were associated with success of therapy (Table 2). On univariate analysis, following factors were found to be associated with success of therapy: low CTP score,
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low MELD score, low bilirubin levels, high albumin levels, low INR, absence of ascites, and
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absence of decompensation (Table 2). When these factors were entered into multivariate analysis by binary logistic regression (Table 3), only high albumin level was found to be
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independently associated with success of therapy [odds ratio 2.1 (95% CI 1.2, 3.9)]. When ROC curve was prepared to find out the utility of serum albumin level in predicting the success of
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therapy the area under ROC curve (AUROC) was 0.716 (95% CI 0.604, 0.828; p=0.001). The
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maximum value of Youden's index corresponded to a serum albumin level of 3.5 g/dL. Thus a cut-off level of ≥3.5 g/dL of serum albumin best predicted the success of therapy with a PPV of
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91% (95% CI 79%, 96%) (Table 4).
Causes of deaths
In the whole cohort of 103 patients, a total of 11 (11%) patients had died during the study period. Ten (90%) of these deaths had occurred in the decompensated cirrhosis group and one death occurred in the control group due to decompensation. The causes of deaths in the decompensated cirrhosis were complications of end-stage liver disease (hepatorenal syndrome, sepsis, hepatic encephalopathy, and multi-organ failure). On comparison of baseline factors between patients who died (n=10) and those who survived (n=37) in the decompensated cirrhosis group, it was found that none of the baseline parameter was significantly different.
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Changes in CTP and MELD scores
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The baseline CTP score in patients with decompensated cirrhosis was 8 (range 7-12) and MELD was 13 (6-25). There was significant improvement in CTP and MELD score in patients who
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achieved SVR (n=27); while there was no improvement in CTP and MELD scores of surviving
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patients who did not achieve SVR (n=10)(Figure 3).
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DISCUSSION
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To summarize the results, our study showed that a 24-week course of Sofosbuvir plus Ribavirin in decompensated HCV cirrhosis could lead to SVR in only 57% of patients. In comparison, 86%
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of compensated cirrhotics and 96% of chronic hepatitis could achieve SVR. The failure of
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therapy in 43% of decompensated cirrhosis patients was either due to non-response, intolerance, or death. We also showed that a serum albumin of more than 3.5 is associated
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with success of antiviral therapy. Successful antiviral therapy also leads to improvement in liver functions in terms of CTP and MELD scores. Thus we suggest that an early initiation of antiviral
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therapy is recommended before decompensation sets in, and precludes successful outcome. Since 1990, IFN based regime were the main stay of treatment with a very low SVR. Since 2001
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Peg IFN was in use in CHC with a SVR of 50%10. Even then almost 75% of the HCV patients remained devoid of antiviral therapy because of varying reasons. Treatment in the decompensated liver disease remained an area of research interest, where use of IFN is either contraindicated or patients are intolerant. In a previous study done from our center published in 2015, we had shown that cirrhosis was the most common presentation of HCV (56%), and only 45% were eligible for Peg-IFN based treatment11. Thus the introduction of IFN-free treatment regimens was the need of hour in country like India, where majority of HCV patients present late in the course of their disease. Availability of DAAs was the major breakthrough in HCV treatment. The structure of HCV virus consists of structural and nonstructural proteins. DAAs target molecular protein structures
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specific to HCV thereby hindering viral replication. Bocepravir and telepravir, the first DAAs, were available since 201112. FDA approved Sofosbuvir in 201313. Currently there are four categories of DAAs: NS5A, NS5B, NS3/4A, and protease inhibitors. NS5A inhibitors available
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include Ledipasvir (LDV), Ombitasvir (ABT-267) and Daclatasvir (DCV). Sofosbuvir (GS-7977) is a
clinical trials, these IFN-free regimens have shown an SVR >90%8.
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NS5B inhibitor14,15. The efficacy of Sofosbuvir based regimens was studied in different phase 3
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The 24-week course of Sofosbuvir plus Ribavirin treatment in our study gives an SVR of 96% in
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chronic hepatitis, 93% in the compensated cirrhotics, and 57% in the decompensated cirrhotics. These results match with the results of various phase 3 trials worldwide. In the study by Osinusi
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et al that included G1 patients with unfavorable treatment characteristics, treated with 24 weeks, the overall SVR was 68%16. In VALANCE trial, SVR in G3 patients with 24 weeks of
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treatment was 85% overall, 91% in non-cirrhotics, and 68% in the cirrhotics17. In the study by
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Doss et al study, SVR in G4 was overall 90%, 93% in non-cirrhotics, and 78% in the cirrhotics18. In the study by Rauene et al in G4 group, SVR was 93% overall9. In the BOSON study, SVR in G2 was 100% and in G3 84%20. The SVR12 in one of the other study, patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0%and 83%21. In the study by Sood A et al, 44.8% were cirrhotics, 14.3% were decompensated. Overall SVR was 95.8%. SVR rates did not differ among different genotypes but were higher in non-cirrhotics22. In advanced HCV related liver diseases, data are scarce, both from western world and from India, regarding the efficacy of 24 weeks of Sofosbuvir plus ribavirin; especially in terms of, stage of disease, improvement achievable in measurable amount (i.e. improvement in CTP
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score or MELD scores), and opportunity to delist from liver transplantation waiting list, after achieving the SVR. While the SVR rate in our study in this group was 57%; we were able to show secondary gains with SVR, i.e. improvement in the CTP and MELD score in SVR achievers
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compared to failure group. With less infrequent side effects of DAA, our study proved the
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safety of these medications in the advanced liver disease. Initial evidence for improvement in liver function in decompensated cirrhosis came from Afdhal et al, who showed that 48 weeks
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treatment with SOF/RBV gave SVR12 rate of 72% and led to significant improvement in ascites, encephalopathy, CTP and MELD scores in the majority. However, only Child's status A and B
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patients were included; there were no Child's C patients in this trial23. In the study conducted
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in Pakistan by Sarwar et al, the study design was similar to our study. There were 51.9% cirrhotics and 17.1% were decompensated. SVR in cirrhotics was 75.4%, in non-cirrhotics was
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93%, in decompensated was 68.8%. This study also showed that there was a statistically
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significant difference among the SVR achievers and failed patients with respect to baseline serum albumin, presence or absence of cirrhosis and CTP scores24. In the study by Reddy et al, the treatment of decompensated HCV patients with different regimens, including Sofosbuvir and Ribavarin showed that these drugs are safe and efficacious in this group with a SVR of 75% in G2. This study showed that lesser the MELD, higher the response rate. In this study serum bilirubin, albumin, MELD scores were improved in significant proportion of patients who achieved SVR25. In the study by Graham R. Foster, an impact of DAA in decompensated patients, overall viral clearance was achieved in 81.6% (90.5% with genotype 1 and 68.8% with genotype 3). MELD scores also improved in treated patients26.
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Host and viral factors predictive of SVR have been studied in the IFN-era and also in the DAAera. In the IFN plus ribavirin related regimens, the genotype, the pretreatment viral load, virological response during the treatment, age, sex, race, degree of fibrosis, IL 28B
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polymorphisms, insulin resistance, vitamin D status, liver cirrhosis stage, all considered as
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individual factors predicting the response to treatment27. The same does not hold good in the DAA era. The most important factor that affects the response rate in the DAA era is liver status.
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Both chronic hepatitis and the compensated cirrhotics showed a better SVR rate than the decompensated cirrhotics in our study. In NEUTRINO trial, the variables associated with therapy
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response were cirrhosis, IL28B (rs12979860) genotype and ribavirin exposure. In FISSION study,
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the predictive factors associated with SVR12 were HCV genotype, presence of cirrhosis, HCVRNA viral load at baseline and ribavirin exposure. In both NEUTRINO and FISSION trials known
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variables such as older age, black race (self-reported), body mass index ≥ 30 kg/m2 that are
SVR28.
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commonly associated with failure of previous IFN-based treatments were not associated with
In the present study, in the univariate analysis, CTP, MELD, bilirubin, INR, albumin, were considered as a predictors of response. On multivariate analysis, only the serum albumin pretreatment, was the independent factor predictive of response. The area under ROC curve for pretreatment serum albumin was 0.716. We found that if the serum albumin levels were > 3.5 before the treatment, higher rates of SVR can be predicted. Our results were consistent with results from other studies. In the study of Graham R. Foster, an impact of DAA in decompensated patients, baseline serum albumin, serum sodium and age came out as predictive factors of response to therapy. Patients with initial serum albumin <35 g/L, aged >65
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or with low (<135 mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy26. In the study conducted in Pakistan by Sarwar et al, serum albumin of < 3.5gm/dL and CTP score >6 was seen in the failed candidates24.
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The results from treatment with double DAA regime using Ledspavir and Daclatasavir are more
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promising as per the phase 3 and real time experiences from western population in both compensated and decompensated group29,30. SOLAR 2, ALLY 1 studies in the decompensated
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HCV, treated with Daclatasavir or Ledspavir along with the Sofosbuvir and Ribavarin showed an
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overall good SVR (85-88%in G1 and 57% in G4)31,32. The SOLAR-2 study could also show improvement of MELD- and Child-Pugh Scores in the treated patients. The same were not
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available in India when this study was undertaken. The results from pan-genotypic regime using the valpatasavir is still further area of interest, which can avoid the need of genotyping, cost
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burden to patients33,34. The same has just been launched in India, and results are awaited.
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There are two limitations in our study. First, this study was conducted when only Sofosbuvir was available in India. With the availability of newer DAAs like ledipasvir, daclatasavir and valpatasavir, the SVR rate in decompensated cirrhosis is expected to be much better. Second limitation is small sample size. We recommend a further study on larger sample size to validate the findings of our study.
In conclusion, patients with decompensated cirrhosis show a poorer response to antiviral therapy and a 24-week course of Sofosbuvir plus Ribavirin could lead to SVR in only 57% of patients. The reasons for failure of therapy in these patients are non-response, intolerance, and death due to advanced liver disease. Of all characteristics of poor liver function in decompensated cirrhosis, we found that serum albumin is a good surrogate marker for
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expected success or failure of therapy. A serum albumin of more than 3.5 g/dL is associated with success of antiviral therapy. Successful antiviral therapy also leads to improvement in liver functions. Thus we propose that an early initiation of antiviral therapy is essential before
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decompensation sets in and precludes successful outcome.
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18. Doss W, Shiha G, Hassany M,et al.Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4.J Hepatol 2015;63:581–585. 19. Ruane PJ, Ain D, Stryker R,et al.Sofosbuvir plus ribavirin for thetreatment of chronic genotype 4hepatitis C virus infection in patientsof Egyptian ancestry.J Hepatol 2015;62: 1040–6 20. Foster GR, Pianko S, Brown A,et al.Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatmentexperienced patients with cirrhosis and hepatitis C virus genotype 2 infection.Gastroenterology2015;149: 1462–70 21.Tania M Welzel , Effectiveness and safety of sofosbuvir plus ribavirinfor the treatment of HCV genotype 2 infection:results of the real-world, clinical practice HCV-TARGET study, Gut2016;0:1–9. 22.Sood A et al,Results of sofosbuvir-based combination therapy for chronic hepatitis C cohort of Indian patients in real-life clinical practice. J Gastroenterol Hepatol. 2017 Apr;32(4):894-900. 23.Afdhal N. Effect of long term viral suppression with sofosbuvir and ribavirin on hepatic venous pressure gradient in HCV infected patients.In: 50th EASL liver congress April LP13. 2015. 24.Shahid Sarwar, Anwaar A. Khan. Sofosbuvir based therapy in Hepatitis C patients with and without cirrhosis: Is there difference?. Pak J Med Sci 2017 Vol. 33 No. 1 25.R. Reddy et al, All oral hcv therapy is safe and effective in patients with decompensated cirrhosis: interim report from the HCV-target real world experience.Journal of Hepatology 2015vol. 62 | S187–S212 26.Graham R. Foster et al, Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.Journal of Hepatology 2016vol. 64. 1224–1231 27. Yan Zhu, Song Chen. Antiviral treatment of hepatitis C virus infection and factors affecting efficacy .World J Gastroenterol 2013 December 21; 19(47): 8963-8973) 28. Lourianne Nascimento Cavalcante, André Castro Lyra. Predictive factors associated with hepatitis C antiviral therapy response.World J Hepatol 2015 June 28; 7(12): 1617-1631) 29.Afdhal N, Zeuzem S, Kwo P,et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1infection. N Engl J Med2014;370:1889–98. 30. Afdhal N, Reddy KR, Nelson DR,et al.Ledipasvir and sofosbuvir for previously treated HCV genotype 1infection. N Engl J Med2014;370:1483–93. 31.Manns, M et al.Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver transplantation patients with HCV infection: Preliminary results of the prospective SOLAR 2 trial. In Proceedings of the EASL 2015, Vienna, Austria, 22–26 April 2015. Int. J. Mol. Sci. 2015, 16 18051 32.Poordad et al, Daclatasvir, sofosbuvir and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: Phase 3 ALLY-1 STUDY. In Proceedings of the EASL 2015, Vienna, Austria, 22–26 April 2015 33.Feld JJ, Jacobson IM, Hezode C,et al.Sofosbuvir and velpatasvir for HCVGenotype 1, 2, 4, 5, and 6 Infection.NEngl J Med2015;373: 2599–607 34.Curry MP, O’Leary JG, Bzowej N,et al.Sofosbuvir and velpatasvir forHCV in patients with decompensatedcirrhosis.N Engl J Med2015;373:2618–28
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TABLES Table1: Baseline charecteristics of HCV patients treated with Sofosbuvir + Ribavarin for 24 weeks
(64%) (36%)
23 5
(82%) (18%)
10 37 5 4×10
(21%) (79%) 1 6 (3×10 -9×10 )
8 20 5 7×10
(29%) (71%) 3 7 (6×10 -3×10 )
38 9 8 13 2.0 2.9 1.3 11 106 1.0
(81%) (19%) (7-12) (6-25) (0.4-12.0) (1.6-4.8) (0.9-3.6) (7-16) (35-309) (0.4-1.8)
24 4 5* 7* 1.0* 3.6* 1.0* 13* 170* 1.0
16 31
(34%) (66%)
42 5 42 5
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30 17
Chronic hepatitis (noncirrhotic) (n=28, controls) 50 (18-65) 16 12
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(n=28, controls) 53 (26-76)
(57%) (43%)
(29%) (71%) 3 7 (2×10 -2×10 )
(86%) (14%) (5-6) (6-13) (0.3-2.1) (3.0-4.8) (1.0-1.7) (7-16) (110-290) (0.6-1.0)
23 5 5* 6* 1.0* 3.6* 1.0* 12* 184* 0.8
(82%) (18%) (5-6) (6-20) (0.4-1.5) (3.0-4.8) (0.8-1.4) (9-17) (102-340) (0.5-4.0)
28* 0
(100%) (0%)
28* 0
(100%) (0%)
(89%) (11%)
28 0
(100%) (0%)
28 0
(100%) (0%)
(89%) (11%)
26 2
(93%) (7%)
29 0
(100%) (0%)
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8 20 5 6×10
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Males Females Genotype 1 and 4 2 and 3 HCV RNA Prior treatment Treatment naïve Treatment experienced CTP score MELD Bilirubin Albumin INR Hemoglobin Platelets Creatinine Ascites Absent Present Encephalopathy Never had encephalopathy Had encephalopathy Variceal bleeding Never bled Past bleeder
Compensated cirrhosis
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Age Gender
Decompensated cirrhosis (n=47, cases) 50 (29-82)
*P<0.05 in comparison to decompensated cirrhosis
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Table 2: Univariate analysis of factors influencing success of therapy
50
(18-68)
0.951 0.806
52 26
(67%) (33%)
18 7
(72%) (28%)
20 58 5×105
(26%) (74%) (3×101-3×107)
6 19 5×105
(24%) (76%) (6×103-7×106)
64 14 6 7 1.0 3.4 1.0 12 168 1.0
(82%) (18%) (5-11) (6-22) (0.3-8.0) (1.6-4.8) (0.8-2.2) (8-17) (67-340) (0.5-4.0)
21 4 7 13 2.0 3.1 1.3 11 107 0.9
(84%) (16%) (5-12) (6-25) (0.3-12.0) (1.3-4.7) (1.0-3.6) (7-15) (35-309) (0.4-1.6)
60 18
(77%) (23%)
12 13
(48%) (52%)
76 2
(97%) (3%)
22 3
(88%) (12%)
(94%) (6%)
23 2
(92%) (8%)
(35%) (65%)
20 5
(80%) (20%)
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P value
1.000
73 5 27 51
0.940 1.000
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Males Females Genotype 1 and 4 2 and 3 HCV RNA Prior treatment Treatment naïve Treatment experienced CTP score MELD Bilirubin Albumin INR Hemoglobin Platelets Creatinine Ascites Absent Present Encephalopathy Never had encephalopathy Had encephalopathy Variceal bleeding Never bled Past bleeder Groups Decompensated cirrhosis Controls
Failed therapy* (n=25)
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Age Gender
Successful therapy (i.e. achieved SVR) (n=78) 51 (25-82)
<0.001 <0.001 0.002 0.001 0.002 0.177 0.076 0.283 0.011
0.091
0.676
<0.001
*Failed therapy patients include those who failed to achieve SVR or ETR (non-responders), those who were intolerant to therapy, and those who died.
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Table 3: Multivariate analysis by binary logistic regression of factors influencing success of therapy Wald
df
P value
Exp(B)
0.181 -1.504 0.179 -0.342 0.764 -2.378 0.020
0.269 0.984 0.164 0.228 0.304 1.600 0.606
0.456 2.339 1.199 2.240 6.343 2.208 0.001
1 1 1 1 1 1 1
0.500 0.126 0.274 0.134 0.012 0.137 0.974
1.199 0.222 1.197 0.711 2.148 0.093 1.020
95% CI for EXP(B) Lower
Upper
0.708 0.032 0.868 0.454 1.185 0.004 0.311
2.030 1.527 1.650 1.112 3.894 2.135 3.348
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S.E.
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CTP score Decompensated cirrhosis MELD score Bilirubin Albumin INR No ascites
B
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Table 4: Predictive values of serum albumin level of ≥3.5 g/dL for predicting success of antiviral therapy. Total (n)
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
Accuracy (95% CI)
LR+ (95% CI)
LR(95% CI)
4 21 25
43 60 103
50% (38%-62%)
84% (64%-95%)
91% (79%-96%)
35% (29%-42%)
77% (72%-82%)
3.1 (1.2-7.9)
0.6 (0.4-0.8)
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Failed thera py (n)
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≥3.5 <3.5 Total
Succes sful thera py (n) 39 39 78
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Serum album in (g/dL)
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FIGURES Figure 1: Flow of patients
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Figure 2: ROC curve for serum albumin as a predictor of successful therapy
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Figure 3: Change in CTP and MELD scores in decompensated cirrhosis group
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ABBREVIATIONS CBC: Complete blood count
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CHC: Chronic Hepatitis C CTP: Child Turcotte Pugh
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DAA: Direct-Acting Antivirals
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ETR: End of Treatment Response GFR: Glomerular filtration rate
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HBsAg: Hepatitis B surface antigen HBV: Hepatitis B virus
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HCC: Hepatocellular carcinoma HCV: Hepatitis C virus
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LFT: Liver function test
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HIV: Human immunodeficiency virus
MELD: Model for Endstage Liver Disease PegIFN: Pegylated Interferon RFT: Renal function test RNA: Ribo-nucleic acid
RVR: Rapid Virological Response SOF: Sofosbuvir
SVR: Sustained Virological Response UGI: Upper gastro-intestinal USG: Ultrasonography
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S0973-6883(18)30040-9 https://doi.org/doi:10.1016/j.jceh.2018.02.009 JCEH 525
To appear in: Received date: Revised date: Accepted date:
2-7-2017 31-1-2018 20-2-2018
Please cite this article as:
RESULTS OF SOFOSBUVIR PLUS RIBAVIRIN IN PATIENTS WITH HEPATITIS C RELATED DECOMPENSATED CIRRHOSIS Naveen TMU, Ashish Kumar, Praveen Sharma, Vikas Singla, Naresh Bansal, Anil Arora
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Short title: Sofosbuvir plus ribavirin in decompensated cirrhosis
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Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
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Total number of Tables: 4 Number of figures: 3 Source(s) of support: Nil Conflict of interest: None
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Correspondence: Prof. Anil Arora, MD, DM Chairman Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences Ganga Ram Institute for Postgraduate Medical Education & Research (GRIPMER) Sir Ganga Ram Hospital Rajinder Nagar New Delhi, 110 060 India Email: [email protected] Fax: +91-11-25861002
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KEYWORDS Sofosbuvir; direct acting antivirals; decompensated cirrhosis; ascites; HCV
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ABSTRACT BACKGROUND: Sofosbuvir (SOF), a direct acting antiviral (DAA), has revolutionized the
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treatment of chronic hepatitis C virus (HCV) infection. However, data is scarce about efficacy of
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SOF plus ribavarin (RBV) in Indian patients with decompensated cirrhosis. We evaluated the efficacy of SOF plus RBV in decompensated cirrhosis, and compared the outcome with
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compensated cirrhosis and non-cirrhotics.
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PATIENTS AND METHODS: Consecutive decompensated cirrhotic patients of chronic HCV with detectable HCV RNA were treated with 24-week course of SOF (400 mg) plus weight based RBV.
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SVR, CTP and MELD scores were assessed at 36 weeks (i.e. 12 weeks after completion of therapy). Non-cirrhotic chronic hepatitis C patients and patients with compensated cirrhosis
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treated with SOF plus RBV during the same period were used as controls. During the period of
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this study Ledipasvir and Daclatasvir were not available in India. RESULTS: A total of 47 patients [median age 50 (29-82) years, 64% males] with decompensated cirrhosis were included as ‘cases’ in the study; while, 27 patients with compensated cirrhosis and 29 patients with chronic hepatitis were included as ‘controls’. Age, gender, HCV RNA levels, and genotype distribution were similar in cases and controls. The median CTP and MELD scores of cases were 8 (7-12) and 13 (6-25), respectively. Among cases 39 (83%) could complete the therapy, while 1 (2%) was intolerant and 7 (15%) died before completion of therapy. ETR was achieved in 37/39 (95%) cases. Of these, another 3 died before SVR, and 7 failed to achieve SVR, thus 27/34 (79%) could achieve SVR. Thus according to intention-to-treat analysis, only 27/47 (57%) cases could achieve SVR. In comparison, 24/28 (86%) compensated cirrhotics and
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27/28 (96%) of chronic hepatitis achieved SVR. There was a significant improvement in mean CTP score in cases who achieved SVR (p<0.01) compared to those who did not achieve SVR/ETR. On multivariate analysis the only independent factor influencing successful outcome patients
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was a serum albumin >3.5 g/dL.
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CONCLUSIONS: A 24-week course of Sofosbuvir plus Ribavirin in decompensated HCV cirrhosis could lead to SVR in only 57% of patients. The failure of therapy in 43% patients was either due
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to non-response, intolerance, or death. A serum albumin of more than 3.5 is associated with
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success of antiviral therapy. Thus an early initiation of antiviral therapy is recommended before
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decompensation sets in as it precludes successful outcome.
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INTRODUCTION
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It is estimated that around 170 million people worldwide are affected with the Hepatitis C virus (HCV) infection1. HCV infection leads to a slowly progressive liver disease. Cirrhosis occurs
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usually around 20-30 years after the infection2. The rate of decompensation is 3.9% per year,
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and the hepatocellular carcinoma (HCC) rate is 3% per year3. As most patients are
asymptomatic for several years, early diagnosis remains a challenge. Stabilization of the liver
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functions is an important goal among both groups of compensated HCV infection and decompensated patients, who are not candidates for liver transplantation, whereas, prevention
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of HCV recurrence is the goal in post-liver transplantation patients4. Sustained virological response (SVR) is tantamount to cure in anti-HCV treatment. SVR at
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present is defined as aviremia 12 weeks after the completion of antiviral therapy for chronic HCV infection5,6,7. Till recently Interferon (IFN) based treatment was the standard of care in anti-HCV treatment. Direct Acting Antivirals (DAA) were the major breakthrough in the treatment of HCV infection. Sofosbuvir is an important DAA, present in almost all DAA regimens. Multiple studies have shown that the efficacy of IFN-free regimens, as studied in different phase-3 trails is >95% SVR rate in patients with chronic hepatitis and compensated cirrhosis8,9. However data regarding efficacy of DAAs in decompensated cirrhosis patients
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scarce, especially from India. This study was undertaken to study the efficacy of Sofosbuvir plus Ribavarin in decompensated HCV cirrhosis patients from India.
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PATIENTS AND METHODS
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Study Setting The study was conducted from May 2015 to June 2016, in patients attending inpatients or
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outpatients’ department of Sir Ganga Ram Hospital, New Delhi. The Ethics Committee of the hospital approved the study and a written informed consent was obtained from all the
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participants. The study conformed to the Helsinki declaration of 1975 as revised in 1983.
Inclusion Criteria
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Patients
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Consecutive decompensated cirrhotic patients of chronic HCV with detectable HCV RNA were
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included in the study as ‘cases’. Decompensated cirrhosis was defined as Child B or C with history of ascites, encephalopathy, UGI bleed secondary to varices, or jaundice. Non-cirrhotic chronic hepatitis C patients and patients with compensated cirrhosis treated with SOF plus RBV during the same period were used as ‘controls’. Both cases and controls were ≥18 years old.
Exclusion Criteria
Patients with pregnancy; glomerular filtration rate (GFR) less than 30 mL/min; HBV or HIV Coinfection; hepatocellular carcinoma; expected life span of less than one year due to various comorbidities; refusal to participate; contraindication to the use of Ribavarin; and patients on
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anticonvulsants (phenytoin, carbamazepine), Rifabutin, Rifampicin, Amiadarone were excluded
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from the study.
Evaluation
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Each patient underwent detailed evaluation in form of history, physical examination, and
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relevant investigations. History of previous upper and lower GI bleeds, hepatic encephalopathy, ascites, other co-morbidities like diabetes, hypertension, HIV, hepatitis B, chronic kidney
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disease, liver or kidney transplantation were obtained from all patients. History of current use of amiadarone, carbamazepine, phenytoin, rifampicin, and rifabutin were also obtained. Past
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history of medication use for HCV, its details with outcome were taken. All patients underwent following investigations: CBC, LFT, RFT, HBsAg, HIV, USG abdomen, Fibroscan, UGI endoscopy,
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HCV RNA quantitative analysis, and HCV genotype.
Treatment Protocol and Follow-up
All patients (cases and controls) were started with Sofosbuvir and Ribavarin with the intention of 24 weeks of treatment. During the period of this study Ledipasvir and Daclatasvir were not available in India. Female patients of reproductive age group were cautioned not to become pregnant while receiving Ribavirin containing antiviral regimens, and up to 6 months after stopping. Follow-up was done through direct patient visit, telephone call, or email. Follow up was done at 4, 12, 24, and 36 weeks (i.e. 12 week after treatment completion). During each visit patients were assessed for clinical improvement or deterioration and any adverse effects. In
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addition to these scheduled follow-ups, patients also visited or called as and when needed depending on patients’ clinical status. The dose of Ribavarin was modified on follow-up if
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patient developed anemia at any time.
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Primary Objective
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The primary objective of the study was to compare the SVR rate in cases and controls at 12
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Secondary Objectives
The secondary objectives of the study were to assess change in CTP and MELD scores at 12
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influencing achievement of SVR.
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weeks after completion of the treatment in decompensated cirrhosis and to study factors
Statistical Analysis
Continuous data were expressed as median (range) and compared using Mann Whitney U test or Wilcoxon signed rank test. Categorical data were expressed as number (%) and compared using Fisher’s exact test or Pearson chi square test. A p value <0.05 was considered significant. Statistical analysis was conducted using the SPSS 17.0 statistical package (SPSS Inc, Chicago, IL, USA).
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RESULTS
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Patients From May 2015 to June 2016, a total of 55 patients with decompensated cirrhosis with HCV
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infection were screened for the study. However 8 patients were excluded due to following
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reasons: (i) GFR less than 30 mL/min (n=3); (ii) HBsAg or HIV co-infection (n=2); (iii) HCC (n=2); and (iv) Refusal to participate (n=1). Thus remaining 47 patients were included in the study as
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‘cases’. During the same duration, 28 patients of compensated cirrhosis due to HCV and 28 patients of non-cirrhotic chronic hepatitis C were included in the study as ‘controls’.
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The baseline characteristics of included patients are given in table 1. The age, gender
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distribution, genotype, HCV RNA, and prior treatment history were similar in cases and controls.
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The median CTP and MELD scores of cases were 8 (range 7-12) and 13 (6-25), respectively; and these were significantly worse than in controls. Ascites was present in 66% of cases, while none of the controls had ascites. Bilirubin, albumin, INR, hemoglobin and platelet levels were significantly worse in cases as compared to controls.
Treatment and results
All patients (cases and controls) were started with Sofosbuvir and Ribavarin with the intention of 24 weeks of treatment. Among the 47 patient of decompensated cirrhosis group, one patient was intolerant to the antiviral therapy; hence, it was stopped. Remaining 46 patients continued with therapy, however, 7 patients died before completion of 24 weeks of treatment. The cause
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of these deaths were advanced liver disease. Thus a total of only 39 (83%) patients of 47 could complete the 24 weeks of treatment, and these were assessed for ETR. Thirty-seven out of 39 patients (95%) achieved ETR and 2 patients (5%) did not achieve ETR. During follow-up of next
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12 weeks, additionally 3 patients died. Thus only 34 (92%) of 37 patients who had achieved ETR
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could be assessed for SVR. Of these 34 patients only 27 (79%) could achieve SVR and rest 7 (21%) could not achieve SVR.
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Among controls, all 27/28 (96%) patients with compensated cirrhosis could complete 24 weeks
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of therapy, while one patient died due to development of rapid decompensation following HCC (which was not detected at baseline). All the remaining 27 patients (100%) who completed
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therapy achieved ETR. After 12 week follow up 24/27 (89%) could achieve SVR and 3/27 (11%) could not achieve SVR. Of 28 patients with chronic hepatitis (non-cirrhotics), all (100%) could
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complete 24 weeks of therapy. These 28 patients were assessed for ETR and 27 (96%) achieved
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ETR; and of these 27 patients assessed for SVR, all of them (100%) achieved SVR. Thus according to intention-to-treat analysis only 27 (57%) out 47 decompensated cirrhotics (cases) could achieve SVR and the rest 20 (43%) failed therapy either due to non-response, intolerance or death. In contrast 24/28 (86%) of compensated cirrhosis and 27/28 (96%) of chronic hepatitis were able to achieve SVR.
Factors influencing success of therapy Out of the total cohort of 103 patients (47 cases and 56 controls), 78 (76%) had successfully achieved SVR, while rest 25 (24%) failed the therapy due to following reasons: non-response
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(n=13), intolerance to therapy (n=1), and death (n=11). Various baseline factors were analyzed to determine which factors were associated with success of therapy (Table 2). On univariate analysis, following factors were found to be associated with success of therapy: low CTP score,
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low MELD score, low bilirubin levels, high albumin levels, low INR, absence of ascites, and
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absence of decompensation (Table 2). When these factors were entered into multivariate analysis by binary logistic regression (Table 3), only high albumin level was found to be
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independently associated with success of therapy [odds ratio 2.1 (95% CI 1.2, 3.9)]. When ROC curve was prepared to find out the utility of serum albumin level in predicting the success of
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therapy the area under ROC curve (AUROC) was 0.716 (95% CI 0.604, 0.828; p=0.001). The
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maximum value of Youden's index corresponded to a serum albumin level of 3.5 g/dL. Thus a cut-off level of ≥3.5 g/dL of serum albumin best predicted the success of therapy with a PPV of
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91% (95% CI 79%, 96%) (Table 4).
Causes of deaths
In the whole cohort of 103 patients, a total of 11 (11%) patients had died during the study period. Ten (90%) of these deaths had occurred in the decompensated cirrhosis group and one death occurred in the control group due to decompensation. The causes of deaths in the decompensated cirrhosis were complications of end-stage liver disease (hepatorenal syndrome, sepsis, hepatic encephalopathy, and multi-organ failure). On comparison of baseline factors between patients who died (n=10) and those who survived (n=37) in the decompensated cirrhosis group, it was found that none of the baseline parameter was significantly different.
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Changes in CTP and MELD scores
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The baseline CTP score in patients with decompensated cirrhosis was 8 (range 7-12) and MELD was 13 (6-25). There was significant improvement in CTP and MELD score in patients who
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achieved SVR (n=27); while there was no improvement in CTP and MELD scores of surviving
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patients who did not achieve SVR (n=10)(Figure 3).
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DISCUSSION
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To summarize the results, our study showed that a 24-week course of Sofosbuvir plus Ribavirin in decompensated HCV cirrhosis could lead to SVR in only 57% of patients. In comparison, 86%
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of compensated cirrhotics and 96% of chronic hepatitis could achieve SVR. The failure of
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therapy in 43% of decompensated cirrhosis patients was either due to non-response, intolerance, or death. We also showed that a serum albumin of more than 3.5 is associated
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with success of antiviral therapy. Successful antiviral therapy also leads to improvement in liver functions in terms of CTP and MELD scores. Thus we suggest that an early initiation of antiviral
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therapy is recommended before decompensation sets in, and precludes successful outcome. Since 1990, IFN based regime were the main stay of treatment with a very low SVR. Since 2001
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Peg IFN was in use in CHC with a SVR of 50%10. Even then almost 75% of the HCV patients remained devoid of antiviral therapy because of varying reasons. Treatment in the decompensated liver disease remained an area of research interest, where use of IFN is either contraindicated or patients are intolerant. In a previous study done from our center published in 2015, we had shown that cirrhosis was the most common presentation of HCV (56%), and only 45% were eligible for Peg-IFN based treatment11. Thus the introduction of IFN-free treatment regimens was the need of hour in country like India, where majority of HCV patients present late in the course of their disease. Availability of DAAs was the major breakthrough in HCV treatment. The structure of HCV virus consists of structural and nonstructural proteins. DAAs target molecular protein structures
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specific to HCV thereby hindering viral replication. Bocepravir and telepravir, the first DAAs, were available since 201112. FDA approved Sofosbuvir in 201313. Currently there are four categories of DAAs: NS5A, NS5B, NS3/4A, and protease inhibitors. NS5A inhibitors available
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include Ledipasvir (LDV), Ombitasvir (ABT-267) and Daclatasvir (DCV). Sofosbuvir (GS-7977) is a
clinical trials, these IFN-free regimens have shown an SVR >90%8.
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NS5B inhibitor14,15. The efficacy of Sofosbuvir based regimens was studied in different phase 3
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The 24-week course of Sofosbuvir plus Ribavirin treatment in our study gives an SVR of 96% in
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chronic hepatitis, 93% in the compensated cirrhotics, and 57% in the decompensated cirrhotics. These results match with the results of various phase 3 trials worldwide. In the study by Osinusi
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et al that included G1 patients with unfavorable treatment characteristics, treated with 24 weeks, the overall SVR was 68%16. In VALANCE trial, SVR in G3 patients with 24 weeks of
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treatment was 85% overall, 91% in non-cirrhotics, and 68% in the cirrhotics17. In the study by
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Doss et al study, SVR in G4 was overall 90%, 93% in non-cirrhotics, and 78% in the cirrhotics18. In the study by Rauene et al in G4 group, SVR was 93% overall9. In the BOSON study, SVR in G2 was 100% and in G3 84%20. The SVR12 in one of the other study, patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0%and 83%21. In the study by Sood A et al, 44.8% were cirrhotics, 14.3% were decompensated. Overall SVR was 95.8%. SVR rates did not differ among different genotypes but were higher in non-cirrhotics22. In advanced HCV related liver diseases, data are scarce, both from western world and from India, regarding the efficacy of 24 weeks of Sofosbuvir plus ribavirin; especially in terms of, stage of disease, improvement achievable in measurable amount (i.e. improvement in CTP
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score or MELD scores), and opportunity to delist from liver transplantation waiting list, after achieving the SVR. While the SVR rate in our study in this group was 57%; we were able to show secondary gains with SVR, i.e. improvement in the CTP and MELD score in SVR achievers
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compared to failure group. With less infrequent side effects of DAA, our study proved the
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safety of these medications in the advanced liver disease. Initial evidence for improvement in liver function in decompensated cirrhosis came from Afdhal et al, who showed that 48 weeks
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treatment with SOF/RBV gave SVR12 rate of 72% and led to significant improvement in ascites, encephalopathy, CTP and MELD scores in the majority. However, only Child's status A and B
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patients were included; there were no Child's C patients in this trial23. In the study conducted
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in Pakistan by Sarwar et al, the study design was similar to our study. There were 51.9% cirrhotics and 17.1% were decompensated. SVR in cirrhotics was 75.4%, in non-cirrhotics was
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93%, in decompensated was 68.8%. This study also showed that there was a statistically
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significant difference among the SVR achievers and failed patients with respect to baseline serum albumin, presence or absence of cirrhosis and CTP scores24. In the study by Reddy et al, the treatment of decompensated HCV patients with different regimens, including Sofosbuvir and Ribavarin showed that these drugs are safe and efficacious in this group with a SVR of 75% in G2. This study showed that lesser the MELD, higher the response rate. In this study serum bilirubin, albumin, MELD scores were improved in significant proportion of patients who achieved SVR25. In the study by Graham R. Foster, an impact of DAA in decompensated patients, overall viral clearance was achieved in 81.6% (90.5% with genotype 1 and 68.8% with genotype 3). MELD scores also improved in treated patients26.
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Host and viral factors predictive of SVR have been studied in the IFN-era and also in the DAAera. In the IFN plus ribavirin related regimens, the genotype, the pretreatment viral load, virological response during the treatment, age, sex, race, degree of fibrosis, IL 28B
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polymorphisms, insulin resistance, vitamin D status, liver cirrhosis stage, all considered as
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individual factors predicting the response to treatment27. The same does not hold good in the DAA era. The most important factor that affects the response rate in the DAA era is liver status.
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Both chronic hepatitis and the compensated cirrhotics showed a better SVR rate than the decompensated cirrhotics in our study. In NEUTRINO trial, the variables associated with therapy
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response were cirrhosis, IL28B (rs12979860) genotype and ribavirin exposure. In FISSION study,
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the predictive factors associated with SVR12 were HCV genotype, presence of cirrhosis, HCVRNA viral load at baseline and ribavirin exposure. In both NEUTRINO and FISSION trials known
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variables such as older age, black race (self-reported), body mass index ≥ 30 kg/m2 that are
SVR28.
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commonly associated with failure of previous IFN-based treatments were not associated with
In the present study, in the univariate analysis, CTP, MELD, bilirubin, INR, albumin, were considered as a predictors of response. On multivariate analysis, only the serum albumin pretreatment, was the independent factor predictive of response. The area under ROC curve for pretreatment serum albumin was 0.716. We found that if the serum albumin levels were > 3.5 before the treatment, higher rates of SVR can be predicted. Our results were consistent with results from other studies. In the study of Graham R. Foster, an impact of DAA in decompensated patients, baseline serum albumin, serum sodium and age came out as predictive factors of response to therapy. Patients with initial serum albumin <35 g/L, aged >65
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or with low (<135 mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy26. In the study conducted in Pakistan by Sarwar et al, serum albumin of < 3.5gm/dL and CTP score >6 was seen in the failed candidates24.
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The results from treatment with double DAA regime using Ledspavir and Daclatasavir are more
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promising as per the phase 3 and real time experiences from western population in both compensated and decompensated group29,30. SOLAR 2, ALLY 1 studies in the decompensated
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HCV, treated with Daclatasavir or Ledspavir along with the Sofosbuvir and Ribavarin showed an
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overall good SVR (85-88%in G1 and 57% in G4)31,32. The SOLAR-2 study could also show improvement of MELD- and Child-Pugh Scores in the treated patients. The same were not
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available in India when this study was undertaken. The results from pan-genotypic regime using the valpatasavir is still further area of interest, which can avoid the need of genotyping, cost
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burden to patients33,34. The same has just been launched in India, and results are awaited.
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There are two limitations in our study. First, this study was conducted when only Sofosbuvir was available in India. With the availability of newer DAAs like ledipasvir, daclatasavir and valpatasavir, the SVR rate in decompensated cirrhosis is expected to be much better. Second limitation is small sample size. We recommend a further study on larger sample size to validate the findings of our study.
In conclusion, patients with decompensated cirrhosis show a poorer response to antiviral therapy and a 24-week course of Sofosbuvir plus Ribavirin could lead to SVR in only 57% of patients. The reasons for failure of therapy in these patients are non-response, intolerance, and death due to advanced liver disease. Of all characteristics of poor liver function in decompensated cirrhosis, we found that serum albumin is a good surrogate marker for
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expected success or failure of therapy. A serum albumin of more than 3.5 g/dL is associated with success of antiviral therapy. Successful antiviral therapy also leads to improvement in liver functions. Thus we propose that an early initiation of antiviral therapy is essential before
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decompensation sets in and precludes successful outcome.
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REFERENCES 1.Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31:1090-1101. 2. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008;48:418-31. 3.Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, et al. (1997)Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 112: 463-472. 4. Luca Saverio Belli et al, Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. Journal of Hepatology 2016 vol. 65:524–531. 5. Pearlman B L,Tarub N,Sustained virological response to antiviral therapy for chronic hepatitis C viral infection. Cure and much more.Clin Infect Dis 2011:52:889-900 6. Renato daltro- oliveira et al, Impact of sustained virological response on quality of life in chronic HCV carriers.Annals of hepatology: may –june,vol 12.no 3,2013;399-407. 7. M. Hedenstierna et al, Long-term follow-up of successful hepatitis C virus therapy:waning immune responses and disappearance of liver disease are consistent with cure Aliment Pharmacol Ther2015;41:532–543. 8. A. Majumdar, M. T. Kitson & S. K. Roberts. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther2016;43:1276–1292 9.European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55(2):245-264 10. Manns MP, Wedemeyer H, Cornberg M.Treating viral hepatitis C: efficacy, side effects, and complications . Gut 2006 ; 55: 1350–1359. 11.Gupta V et al, Journal of Clinical and Experimental Hepatology | June 2015 | Vol. 5 | No. 2 | 134 - 141 12. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med2011; 364: 2405-2416 13. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med2013 14.Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies.Nat Med2013;19: 837–49. 15. Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med2013;368:1907–17. 16. Osinusi A, Meissner EG, Lee YJ,et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.JAMA 2013;310: 804–11. 17. Zeuzem S, Dusheiko GM, Salupere R,et al.Sofosbuvir and ribavirin in HCVgenotypes 2 and 3.N Engl J Med2014;370: 1993–2001
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18. Doss W, Shiha G, Hassany M,et al.Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4.J Hepatol 2015;63:581–585. 19. Ruane PJ, Ain D, Stryker R,et al.Sofosbuvir plus ribavirin for thetreatment of chronic genotype 4hepatitis C virus infection in patientsof Egyptian ancestry.J Hepatol 2015;62: 1040–6 20. Foster GR, Pianko S, Brown A,et al.Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatmentexperienced patients with cirrhosis and hepatitis C virus genotype 2 infection.Gastroenterology2015;149: 1462–70 21.Tania M Welzel , Effectiveness and safety of sofosbuvir plus ribavirinfor the treatment of HCV genotype 2 infection:results of the real-world, clinical practice HCV-TARGET study, Gut2016;0:1–9. 22.Sood A et al,Results of sofosbuvir-based combination therapy for chronic hepatitis C cohort of Indian patients in real-life clinical practice. J Gastroenterol Hepatol. 2017 Apr;32(4):894-900. 23.Afdhal N. Effect of long term viral suppression with sofosbuvir and ribavirin on hepatic venous pressure gradient in HCV infected patients.In: 50th EASL liver congress April LP13. 2015. 24.Shahid Sarwar, Anwaar A. Khan. Sofosbuvir based therapy in Hepatitis C patients with and without cirrhosis: Is there difference?. Pak J Med Sci 2017 Vol. 33 No. 1 25.R. Reddy et al, All oral hcv therapy is safe and effective in patients with decompensated cirrhosis: interim report from the HCV-target real world experience.Journal of Hepatology 2015vol. 62 | S187–S212 26.Graham R. Foster et al, Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.Journal of Hepatology 2016vol. 64. 1224–1231 27. Yan Zhu, Song Chen. Antiviral treatment of hepatitis C virus infection and factors affecting efficacy .World J Gastroenterol 2013 December 21; 19(47): 8963-8973) 28. Lourianne Nascimento Cavalcante, André Castro Lyra. Predictive factors associated with hepatitis C antiviral therapy response.World J Hepatol 2015 June 28; 7(12): 1617-1631) 29.Afdhal N, Zeuzem S, Kwo P,et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1infection. N Engl J Med2014;370:1889–98. 30. Afdhal N, Reddy KR, Nelson DR,et al.Ledipasvir and sofosbuvir for previously treated HCV genotype 1infection. N Engl J Med2014;370:1483–93. 31.Manns, M et al.Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver transplantation patients with HCV infection: Preliminary results of the prospective SOLAR 2 trial. In Proceedings of the EASL 2015, Vienna, Austria, 22–26 April 2015. Int. J. Mol. Sci. 2015, 16 18051 32.Poordad et al, Daclatasvir, sofosbuvir and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: Phase 3 ALLY-1 STUDY. In Proceedings of the EASL 2015, Vienna, Austria, 22–26 April 2015 33.Feld JJ, Jacobson IM, Hezode C,et al.Sofosbuvir and velpatasvir for HCVGenotype 1, 2, 4, 5, and 6 Infection.NEngl J Med2015;373: 2599–607 34.Curry MP, O’Leary JG, Bzowej N,et al.Sofosbuvir and velpatasvir forHCV in patients with decompensatedcirrhosis.N Engl J Med2015;373:2618–28
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TABLES Table1: Baseline charecteristics of HCV patients treated with Sofosbuvir + Ribavarin for 24 weeks
(64%) (36%)
23 5
(82%) (18%)
10 37 5 4×10
(21%) (79%) 1 6 (3×10 -9×10 )
8 20 5 7×10
(29%) (71%) 3 7 (6×10 -3×10 )
38 9 8 13 2.0 2.9 1.3 11 106 1.0
(81%) (19%) (7-12) (6-25) (0.4-12.0) (1.6-4.8) (0.9-3.6) (7-16) (35-309) (0.4-1.8)
24 4 5* 7* 1.0* 3.6* 1.0* 13* 170* 1.0
16 31
(34%) (66%)
42 5 42 5
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30 17
Chronic hepatitis (noncirrhotic) (n=28, controls) 50 (18-65) 16 12
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(n=28, controls) 53 (26-76)
(57%) (43%)
(29%) (71%) 3 7 (2×10 -2×10 )
(86%) (14%) (5-6) (6-13) (0.3-2.1) (3.0-4.8) (1.0-1.7) (7-16) (110-290) (0.6-1.0)
23 5 5* 6* 1.0* 3.6* 1.0* 12* 184* 0.8
(82%) (18%) (5-6) (6-20) (0.4-1.5) (3.0-4.8) (0.8-1.4) (9-17) (102-340) (0.5-4.0)
28* 0
(100%) (0%)
28* 0
(100%) (0%)
(89%) (11%)
28 0
(100%) (0%)
28 0
(100%) (0%)
(89%) (11%)
26 2
(93%) (7%)
29 0
(100%) (0%)
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8 20 5 6×10
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Males Females Genotype 1 and 4 2 and 3 HCV RNA Prior treatment Treatment naïve Treatment experienced CTP score MELD Bilirubin Albumin INR Hemoglobin Platelets Creatinine Ascites Absent Present Encephalopathy Never had encephalopathy Had encephalopathy Variceal bleeding Never bled Past bleeder
Compensated cirrhosis
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Age Gender
Decompensated cirrhosis (n=47, cases) 50 (29-82)
*P<0.05 in comparison to decompensated cirrhosis
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Table 2: Univariate analysis of factors influencing success of therapy
50
(18-68)
0.951 0.806
52 26
(67%) (33%)
18 7
(72%) (28%)
20 58 5×105
(26%) (74%) (3×101-3×107)
6 19 5×105
(24%) (76%) (6×103-7×106)
64 14 6 7 1.0 3.4 1.0 12 168 1.0
(82%) (18%) (5-11) (6-22) (0.3-8.0) (1.6-4.8) (0.8-2.2) (8-17) (67-340) (0.5-4.0)
21 4 7 13 2.0 3.1 1.3 11 107 0.9
(84%) (16%) (5-12) (6-25) (0.3-12.0) (1.3-4.7) (1.0-3.6) (7-15) (35-309) (0.4-1.6)
60 18
(77%) (23%)
12 13
(48%) (52%)
76 2
(97%) (3%)
22 3
(88%) (12%)
(94%) (6%)
23 2
(92%) (8%)
(35%) (65%)
20 5
(80%) (20%)
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P value
1.000
73 5 27 51
0.940 1.000
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Males Females Genotype 1 and 4 2 and 3 HCV RNA Prior treatment Treatment naïve Treatment experienced CTP score MELD Bilirubin Albumin INR Hemoglobin Platelets Creatinine Ascites Absent Present Encephalopathy Never had encephalopathy Had encephalopathy Variceal bleeding Never bled Past bleeder Groups Decompensated cirrhosis Controls
Failed therapy* (n=25)
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Age Gender
Successful therapy (i.e. achieved SVR) (n=78) 51 (25-82)
<0.001 <0.001 0.002 0.001 0.002 0.177 0.076 0.283 0.011
0.091
0.676
<0.001
*Failed therapy patients include those who failed to achieve SVR or ETR (non-responders), those who were intolerant to therapy, and those who died.
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Table 3: Multivariate analysis by binary logistic regression of factors influencing success of therapy Wald
df
P value
Exp(B)
0.181 -1.504 0.179 -0.342 0.764 -2.378 0.020
0.269 0.984 0.164 0.228 0.304 1.600 0.606
0.456 2.339 1.199 2.240 6.343 2.208 0.001
1 1 1 1 1 1 1
0.500 0.126 0.274 0.134 0.012 0.137 0.974
1.199 0.222 1.197 0.711 2.148 0.093 1.020
95% CI for EXP(B) Lower
Upper
0.708 0.032 0.868 0.454 1.185 0.004 0.311
2.030 1.527 1.650 1.112 3.894 2.135 3.348
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S.E.
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CTP score Decompensated cirrhosis MELD score Bilirubin Albumin INR No ascites
B
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Table 4: Predictive values of serum albumin level of ≥3.5 g/dL for predicting success of antiviral therapy. Total (n)
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
Accuracy (95% CI)
LR+ (95% CI)
LR(95% CI)
4 21 25
43 60 103
50% (38%-62%)
84% (64%-95%)
91% (79%-96%)
35% (29%-42%)
77% (72%-82%)
3.1 (1.2-7.9)
0.6 (0.4-0.8)
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Failed thera py (n)
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≥3.5 <3.5 Total
Succes sful thera py (n) 39 39 78
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Serum album in (g/dL)
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FIGURES Figure 1: Flow of patients
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Figure 2: ROC curve for serum albumin as a predictor of successful therapy
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Figure 3: Change in CTP and MELD scores in decompensated cirrhosis group
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ABBREVIATIONS CBC: Complete blood count
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CHC: Chronic Hepatitis C CTP: Child Turcotte Pugh
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DAA: Direct-Acting Antivirals
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ETR: End of Treatment Response GFR: Glomerular filtration rate
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HBsAg: Hepatitis B surface antigen HBV: Hepatitis B virus
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HCC: Hepatocellular carcinoma HCV: Hepatitis C virus
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LFT: Liver function test
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HIV: Human immunodeficiency virus
MELD: Model for Endstage Liver Disease PegIFN: Pegylated Interferon RFT: Renal function test RNA: Ribo-nucleic acid
RVR: Rapid Virological Response SOF: Sofosbuvir
SVR: Sustained Virological Response UGI: Upper gastro-intestinal USG: Ultrasonography
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